Gasdermin D promotes hyperinflammation and immunopathology during severe influenza A virus infection

Excessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a po...

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Vydáno v:Cell death & disease Ročník 14; číslo 11; s. 727 - 11
Hlavní autoři: Rosli, Sarah, Harpur, Christopher M., Lam, Maggie, West, Alison C., Hodges, Christopher, Mansell, Ashley, Lawlor, Kate E., Tate, Michelle D.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 09.11.2023
Springer Nature B.V
Nature Publishing Group
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Antibodies
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell death
Chemokines
Disease resistance
Epithelial cells
Immunology
Infections
Inflammation
Influenza
Influenza A
Interleukins
Leukocytes (neutrophilic)
Life Sciences
Lung diseases
Monocyte chemoattractant protein 1
Neutrophils
Pyroptosis
ISSN:2041-4889, 2041-4889
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Shrnutí:Excessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a potential role for GSDMD in promoting the development of severe IAV disease. IAV infection resulted in cleavage of GSDMD in vivo and in vitro in lung epithelial cells. Mice genetically deficient in GSDMD ( Gsdmd −/− ) developed less severe IAV disease than wildtype mice and displayed improved survival outcomes. GSDMD deficiency significantly reduced neutrophil infiltration into the airways as well as the levels of pro-inflammatory cytokines TNF, IL-6, MCP-1, and IL-1α and neutrophil-attracting chemokines CXCL1 and CXCL2. In contrast, IL-1β and IL-18 responses were not largely impacted by GSDMD deficiency. In addition, Gsdmd −/− mice displayed significantly improved influenza disease resistance with reduced viral burden and less severe pulmonary pathology, including decreased epithelial damage and cell death. These findings indicate a major role for GSDMD in promoting damaging inflammation and the development of severe IAV disease.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06258-1